This continuing research is concerned with metabolic alterations in the brain which occur in experimentally-induced amino acid imbalances. Comprehensive studies are being carried out on the effects of acute and chronic hyperaminoacidemias on processes which may be involved in the regulation of amino acid and protein metabolism in the brain. The amino acids given in excess will include phenylalanine, leucine, histidine and lysine. These amino acids have markedly diverse metabolic properties, but are all involved in aminoacidopathies which are associated with overt brain damage in human infants. The specific points being investigated are: (a) developmental and regional differences in the sensitivity of the brain to alterations in amino acid distribution and metabolism resulting from acute or chronic parenteral administration of an amino acid load, (b) the relationship of the resulting amino acid imbalance to possible variations in the synthesis of specific brain proteins, and (c) the basic metabolic mechanisms underlying these processes. The basic brain mechanisms being investigated in the experimental hyperaminoacidemias include: (a) polyribosomal stability in vivo, (b) initiation of protein synthesis in vitro, and (c) phosphorylation of ribosomal proteins and initiation factors in vivo. In addition, since alterations in the structure and function of brain lysosomes have been observed in experimental hyperaminoacidemia, the possible relationship of these alterations to variations in brain protein metabolism will continue to be explored. It is anticipated that these investigations may help to elucidate the mechanisms involved in the production of metabolic abnormalities which contribute to brain dysfunction in human aminoacidopathies.